The present invention is concerned with side chain aldehydes of 17.beta.-N-alkyl carbamoyl-4-aza-5.alpha.-androst-1-en-3-one compounds as testosterone-5.alpha.-reductase inhibitors for the treatment of benign prostatic hypertrophy.
The art reveals that certain undesirable physiological manifestations, such as ache vulgaris, seborrhea, female hirsutism, male pattern baldness and benign prostatic hypertrophy, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system.
It is now known in the art that the principal mediator of androgenic activity in some target organs is 5.alpha.-dihydrotestosterone, and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It is also known that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation.
For example, U.S. Pat. Nos 4,377,584, 4,220,775, 4,760,071, 4,859,681 and 5,049,562 of Rasmusson et al. describe a group of 4-aza-17.beta.-substituted-5.alpha.-androstan-3-ones which are said to be useful in the treatment of hyperandrogenic conditions. Specifically, U.S. Pat. No. 4,760,071 describes finasteride, which is 17.beta.-(N-tert-butylcarbamoyl)-4-aza-androst-1-ene-3-one, also known as PROSCAR.RTM., recently approved by the FDA for use in benign prostatic hyperplasia therapy.
U.S. Pat. No. 4,845,104 issued Jul. 4, 1989, to Merck & Co., discloses oxidized analogs of 17.beta.-N-(monosubstituted)carbamoyl-4-aza-5.alpha.-androstan-3-ones having utility as highly potent testosterone-5.alpha.-reductase inhibitors and being metabolites resulting from in vivo administration of 7.beta.-(N-t-butylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one.
However, none of the cited references suggest that any of the novel- 17.beta.-N-(monosubstituted) carbamoyl-4-aza-5.alpha.-androst-1-en-3-ones containing an aldehydes-substituted branched alkyl on the 17-position of the present invention would also be a metabolite or have utility in treating benign prostatic hypertrophy. In many cases, the metabolism of an active drug results in deactivation and/or excretion. However, in this case the compounds of the present invention maintain a high level of bioactivity in treated animals.